Delestrogen

CLINICAL PHARMACOLOGY

Endogenous estrogens are largely responsible for the development and maintenance
of the female reproductive system and secondary sexual characteristics. Although
circulating estrogens exist in a dynamic equilibrium of metabolic interconversions,
estradiol is the principal intracellular human estrogen and is substantially
more potent than its metabolites, estrone and estriol, at the receptor level.

The primary source of estrogen in normally cycling adult women is the ovarian
follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the
phase of the menstrual cycle. After menopause, most endogenous estrogen is produced
by conversion of androstenedione, secreted by the adrenal cortex, to estrone
by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone
sulfate, are the most abundant circulating estrogens in postmenopausal women.

Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.

Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

Pharmacokinetics

Absorption

Estrogens used in therapy are well absorbed through the skin, mucous membranes, and gastrointestinal tract. When applied for a local action, absorption is usually sufficient to cause systemic effects. When conjugated with aryl and alkyl groups for parenteral administration, the rate of absorption of oily preparations is slowed with a prolonged duration of action, such that a single intramuscular injection of estradiol valer-ate or estradiol cypionate is absorbed over several weeks.

Distribution

The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.

Metabolism

Exogenous estrogens are metabolized in the same manner as endogenous estrogens.
Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions.
These transformations take place mainly in the liver. Estradiol is converted
reversibly to estrone, and both can be converted to estriol, which is the major
urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate
and glu-curonide conjugation in the liver, biliary secretion of conjugates into
the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal
women, a significant proportion of the circulating estrogens exist as sulfate
conjugates, especially estrone sulfate, which serves as a circulating reservoir
for the formation of more active estrogens.

When given orally, naturally-occurring estrogens and their esters are extensively
metabolized (first pass effect) and circulate primarily as estrone sulfate,
with smaller amounts of other conjugated and unconjugated estro-genic species.
This results in limited oral potency. By contrast, synthetic estrogens, such
as ethinyl estradiol and the nonsteroidal estrogens, are degraded very slowly
in the liver and other tissues, which results in their high intrinsic potency.
Estrogen drug products administered by non-oral routes are not subject to first-pass
metabolism, but also undergo significant hepatic uptake, metabolism, and enterohepatic
recycling.

Excretion

Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.

Drug Interactions

In vitroand in vivo studies have shown that estrogens are metabolized
partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors
of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4 such as St.
John's Wort preparations (Hypericum perforatum), phenobarbital, carbamazepine,
and rifampin may reduce plasma concentrations of estrogens, possibly resulting
in a decrease in therapeutic effects and/or changes in the uterine bleeding
profile. Inhibitors of CYP3A4 such as erythromycin, clar-ithromycin, ketoconazole,
itraconazole, ritonavir and grapefruit juice may increase plasma concentrations
of estrogens and may result in side effects.

Clinical Studies

Women's Health Initiative Studies

The Women's Health Initiative (WHI) enrolled a total of 27,000 predominantly
healthy postmenopausal women to assess the risks and benefits of either the
use of oral 0.625 mg conjugated estrogens (CE) per day alone or the use of oral
0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate (MPA)
per day compared to placebo in the prevention of certain chronic diseases. The
primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal
myocardial infarction and CHD death), with invasive breast cancer as the primary
adverse outcome studied. A "global index" included the earliest occurrence
of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial
cancer, colorec-tal cancer, hip fracture, or death due to other cause. The study
did not evaluate the effects of CE or CE/MPA on menopausal symptoms.

The CE/MPA substudy was stopped early because, according to the predefined
stopping rule, the increased risk of breast cancer and cardiovascular events
exceeded the specified benefits included in the "global index." Results
of the CE/MPA substudy, which included 16,608 women (average age of 63 years,
range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up
of 5.2 years are presented in Table 1 below:

Table 1. RELATIVE AND ABSOLUTE RISK SEEN IN THE CE/MPA SUBSTUDY
OF WHIa

Eventc

Relative Risk CE/MPA vs placebo
at 5.2 Years
(95% CI*)

Placebo
n = 8102

CE/MPA
n = 8506

Absolute Risk per 10,000 Person-years

CHD events

1.29 (1.02-1.63)

30

37

Non-fatal MI

1.32 (1.02-1.72)

23

30

CHD death

1.18 (0.70-1.97)

6

7

Invasive breast cancerb

1.26 (1.00-1.59)

30

38

Stroke

1.41 (1.07-1.85)

21

29

Pulmonary embolism

2.13 (1.39-3.25)

8

16

Colorectal cancer

0.63 (0.43-0.92)

16

10

Endometrial cancer

0.83 (0.47-1.47)

6

5

Hip fracture

0.66 (0.45-0.98)

15

10

Death due to causes other than the events above

0.92 (0.74-1.14)

40

37

Global Indexc

1.15 (1.03-1.28)

151

170

Deep vein thrombosisd

2.07 (1.49-2.87)

13

26

Vertebral fracturesd

0.66 (0.44-0.98)

15

9

Other osteoporotic fracturesd

0.77 (0.69-0.86)

170

131

a adapted from JAMA, 2002; 288:321-333 bincludes metastatic and non-metastatic breast cancer with the
exception of in situ breast cancer c a subset of the events was combined in a "global index",
defined as the earliest occurrence of CHD events, invasive breast cancer,
stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture,
or death due to other causes dnot included in Global Index
*nominal confidence intervals unadjusted for multiple looks and multiple
comparisons

For those outcomes included in the "global index," the absolute excess
risks per 10,000 women-years in the group treated with CE/MPA were 7 more CHD
events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while
absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers
and 5 fewer hip fractures. The absolute excess risk of events included in the
"global index" was 19 per 10,000 women-years. There was no difference
between the groups in terms of all-cause mortality. (SeeBOXED
WARNING, WARNINGS, and PRECAUTIONS.)

Women's Health Initiative Memory Study

The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of CE/MPA (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome) compared with placebo.

After an average follow-up of 4 years, 40 women in the estrogen/progestin group
(45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years)
were diagnosed with probable dementia. The relative risk of probable dementia
in the hormone therapy group was 2.05 (95% CI, 1.21 to 3.48) compared to placebo.
Differences between groups became apparent in the first year of treatment. It
is unknown whether these findings apply to younger postmenopausal women. (See
BOXED WARNING and WARNINGS,
Dementia.)

Last reviewed on RxList: 9/18/2008
This monograph has been modified to include the generic and brand name in many instances.